PROJECT SUMMARY/ ABSTRACT The diagnosis of multiple sclerosis (MS) is currently based on demonstration of dissemination in space (the development of lesions in distinct anatomical locations within the central nervous system) and dissemination in time (development or appearance of new CNS lesions over time). There is no simple laboratory test available for a diagnosis of MS. Advances in MRI have led to more sensitive diagnostic criteria and facilitated earlier diagnosis. Despite some improvements in diagnostic sensitivity, many patients continue to have a delay in diagnosis. Early treatment with DMT prevents relapses and subsequent accumulation of disability ? so diagnostic delay can have severe and life-long consequences. In addition, studies that have informed revisions and validation of the diagnostic criteria were conducted in individuals presenting with typical syndromes (clinically isolated syndrome), diminishing specificity and making the criteria uninformative for the ~50% of patients who are referred for a diagnosis of MS with atypical or non-classical symptoms. The problem of misdiagnosis is significant as approximately 20% of patients referred to an MS center with a previous diagnosis of MS have been found to be misdiagnosed. One feature that helps differentiate MS lesions is the presence of the Central Vein Sign (CVS) on MRI. CVS criteria have been formulated using the presence of CVS in specific lesions to grade an individual MRI study. The CVS is proposed as a diagnostic biomarker with improved sensitivity for a diagnosis of MS, while retaining diagnostic specificity ? all in an-easy-to use diagnostic test that can be applied in patients with both typical and atypical disease presentation. A combination of T2- weighted FLAIR and T2*-weighted segEPI imaging, the methodology we propose for this application, has been shown to be particularly sensitive for the detection of central veins. The CentrAl Vein Sign in MS (CAVS-MS) study seeks to answer whether the central vein sign (CVS) can be used as a sensitive and specific diagnostic marker for a diagnosis of MS. The study will investigate the CVS in a mixed population of participants with typical and atypical clinical presentations including radiological presentations without neurological symptoms. The study will enroll 200 patients with typical clinical presentations and 200 participants with atypical presentations (total 400) who present to an MS center for a diagnostic referral and will follow study participants for up to 24 months to determine the specificity and sensitivity of the central vein sign for a diagnosis of MS using McDonald 2017 at 2 years as the gold standard for diagnosis. The overarching goal of this multi-center proposal is to allow incorporation of the CVS ? an easy-to-measure radiological biomarker ? into the diagnostic criteria for MS, thereby facilitating earlier and more accurate diagnosis. Defining CVS criteria and patterns in typical and atypical MS presentations, as well as determining accuracy and speed of diagnosis, will inform public health interventions in MS.